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Abstract

Objectives: Despite a paucity of published supporting data, 5-aminosalicylate (5-ASA) use in pediatric ulcerative colitis (UC) is common. The present study describes the use and outcome of a large multicenter inception cohort of children with UC treated with 5-ASA.

Methods: Data were obtained from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, a prospective North American observational study of children newly diagnosed as having inflammatory bowel disease ages 16 years or younger. Patient data are recorded at diagnosis, 30 days, and then quarterly. Patients are managed by physician dictate, not protocol. Disease activity is classified by physician global assessment. The primary outcome examined was corticosteroid (CS) free, inactive UC at 1 year following initiation of 5-ASA within 30 days of diagnosis (with or without concomitant CS use) without the need for rescue therapy (immunomodulators, biologics, or colectomy).

Results: Study subjects included 213 patients newly diagnosed as having UC who received oral 5-ASA compounds (115 of whom also received CS) during the first 30 days after diagnosis, and no other oral therapies for the treatment of UC. Of these 213 patients, 86 (40%) were CS free and physician global assessment inactive at 1 year without rescue. Outcome was not associated with disease severity at diagnosis, demographic or laboratory factors examined, or initial dose of 5-ASA used.

Conclusions: Forty percent of children taking 5-ASA as primary maintenance therapy at diagnosis are in CS-free remission after 1 year of treatment. Further pediatric studies will be needed to address whether increased adherence and/or higher dosing schedules will improve outcomes.

Data supporting the use of 5-aminosalicylate (5-ASA) compounds for induction and maintenance therapy in adult ulcerative colitis (UC) are strong (1,2). A recent meta-analysis comparing 5-ASA use with placebo in adults showed that induction and maintenance of remission was significantly higher in patients receiving 5-ASA compounds compared with placebo (3). In the 11 randomized controlled trials included in this meta-analysis, induction of remission was achieved in 40% of patients receiving 5-ASA medications versus 20% receiving placebo. Likewise, maintenance of remission was achieved in 60% receiving 5-ASA medications versus 38% receiving placebo.

In contrast, data supporting the use of 5-aminosalicylate (5-ASA) therapies in pediatric patients are scarce and the widely accepted practice among pediatric clinicians to prescribe these medications is generally based on data extrapolated from adult studies. In 1993, Ferry et al (4) published the only randomized double-blind study to date looking at efficacy of 5-ASA compounds in pediatric UC. Fifty-six children with mild or moderate disease were included in the study and were randomized to take olsalazine (30 mg · kg−1 · day−1) or sulfasalazine (60 mg · kg−1 · day−1). The rate of response or remission at 3 months among patients taking olsalazine was reported to be 39% versus 79% for patients taking sulfasalazine. In 1996, Hyams et al (5) published a retrospective review of outcomes for 171 children with mild, moderate, or severe UC. The majority of patients included in the study were maintained on 5-ASA with or without corticosteroids (CSs) during the first 12 months after diagnosis; only 7% received immunomodulators and 5% required colectomy. At 12 months after diagnosis, 49% of patients within this cohort were in remission excluding those patients who required colectomy.

Given the paucity of pediatric-specific data on the use of 5-ASA medications in UC, the aim of the present study was to determine the outcome following initiation of 5-ASA medications for UC in a large multicenter contemporary inception cohort of pediatric patients. Furthermore, we also sought to identify demographic, clinical, and laboratory factors that may be associated with outcome following 5-ASA therapy in this population.

METHODS

This was a prospective, multicenter, inception cohort study of a subgroup of children with UC enrolled in the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry. The Registry is an ongoing, observational research program started in 2002 that is conducted at pediatric gastroenterology centers in the United States and Canada collectively known as the Pediatric Inflammatory Bowel Disease Collaborative Research Group. Children younger than 16 years newly diagnosed as having inflammatory bowel disease are eligible for enrollment in the Registry through one of the participating sites. Medical data for each enrolled patient are collected from the treating physician and submitted to a centralized data management center. Data are submitted at the time of diagnosis, 30 days after diagnosis, and every 3 months thereafter. All of the patients are managed according to the dictates of their physicians, and not by standardized protocols.

Study Population

Inclusion criteria for the study population included receiving an oral 5-ASA compound within 30 days after diagnosis with or without concomitant CSs; no other concomitant oral or intravenous medication for the treatment of UC during the first 30 days after diagnosis; and a minimum follow-up from diagnosis of 1 year. Patients were excluded from analysis if they did not receive an oral 5-ASA compound within 30 days after diagnosis or received additional “rescue therapies” within 30 days after diagnosis. Rescue therapy was defined as immunomodulators (azathioprine, 6-mercaptopurine, methotrexate), calcineurin inhibitors (cyclosporine, tacrolimus), antitumor necrosis factor-α agents (infliximab or adalimumab), or surgery.

Although rectal therapy usage in study patients is captured in the registry database in a “yes-no” format, data regarding the dose and formulation used were not available, including whether rectal medications were 5-ASA versus steroid based. Rectal therapy usage did not factor into the inclusion or exclusion criteria for the present study.

Outcome Measures

The primary outcome variable was CS-free, rescue-free physician global assessment (PGA) of inactive disease at 1 year following diagnosis. A secondary outcome variable was CS-free, rescue-free PGA of mild disease at 1 year following diagnosis. We also examined potential relations between demographic, clinical, and laboratory features at diagnosis and the primary outcome variable.

Statistical Analysis

Groups were compared using t tests for continuously distributed variables and χ2 and exact tests for categorical variables. Multivariate logistic regression was used to analyze for predictors of our primary outcome. A significance level of 0.05 was used for all of the tests.

Institutional Review Board

The institutional review board at each participating center approved the protocol. Informed consent and, when appropriate, assent was obtained from all of the parents/caregivers and patients enrolled in the Registry in accord with local regulations.

RESULTS

Study Population

From January 2002 to August 2010, a total of 1669 children newly diagnosed as having inflammatory bowel disease were enrolled in the registry from 32 sites in the United States and Canada. Four hundred forty (26%) of these patients were diagnosed as having UC, and 353 had a minimum follow-up of 1 year. After inclusion and exclusion criteria were met, a total of 213 patients were included in our study population. Figure 1 summarizes how the final study population was derived.

As shown in the figure, nonmutually exclusive rescue therapies were received by 69 patients. Rescue therapies received included immunomodulators (n = 57), infliximab (n = 12), calcineurin inhibitors (n = 7), and colectomy (n = 8). Of the 122 patients who were not included because of meeting exclusion criteria and/or not meeting inclusion criteria, 32 patients received oral 5-ASA medications as part of combination therapy during the first 30 days following diagnosis, whereas 90 of these 122 patients were not prescribed 5-ASA as part of the initial regimen. Thus, in this cohort of 353 patients diagnosed as having UC with >1 year of follow-up, oral 5-ASA use as single or combination therapy within the first 30 days following diagnosis was 73%. (This calculation excludes the 18 patients for whom there were insufficient data recorded). The 90 patients who did not receive an oral 5-ASA within the first 30 days following diagnosis include 42 patients who received CS alone during this time, as shown in Figure 1. Of these 42 patients, it should be noted that 29 then went on to receive a 5-ASA medication without other rescue therapies added by the end of the first 3 months after diagnosis.

The clinical and demographic characteristics at diagnosis of the 213 subjects who fulfilled study criteria are shown in Table 1. Of these 213 patients, 98 (46%) received an oral 5-ASA medication without CS within the first 30 days following diagnosis, and 115 (54%) were treated with a 5-ASA plus a CS. There were no significant differences between these groups with respect to mean age at diagnosis, sex distribution, median length of follow-up, the presence of pancolitis versus limited disease, and the mean dosage of 5-ASA that was prescribed; however, the subgroup of study patients who received CS had a significantly higher erythrocyte sedimentation rate (ESR) and platelet count as well as a lower hemoglobin and albumin compared with the patients who were not receiving CS by 30 days after diagnosis. These differences likely reflect the significantly more severe disease activity among the patients who received CS in addition to 5-ASA medications during the first 30 days following diagnosis. Of note, there were no significant differences in initial PGA or initial laboratory markers including hemoglobin, platelet count, ESR, or albumin in patients who received higher doses of 5-ASA (≥60 mg · kg−1 · day−1) compared with patients who received lower doses of 5-ASA (<60 mg · kg−1 · day−1).

We looked at the incidence of rectal therapy in our study group and found it to be 17% at 30 days following diagnosis, and 32% (cumulative) over the first year (Table 2). Overall, patients receiving 5-ASA medications without CS were significantly more likely to also be receiving rectal therapies by 30 days (23% versus 12%, P = 0.04). Broken down by PGA, at 30 days following diagnosis, patients receiving 5-ASA alone presenting with moderate/severe disease were more likely to be receiving rectal therapy at 30 days than patients who received 5-ASA and CS (P = .014). Patients who had received 5-ASA medications without CS by 30 days also had a greater 1-year cumulative use of rectal therapy (39% vs 27%), but the result was not statistically significant. As noted in the methods section of this article, rectal therapy usage in study patients is captured in the registry database in a “yes-no” format. Data regarding the dose and formulation used were not available, including whether the rectal medication was 5-ASA versus steroid based.

Outcome at 1 Year

Of the 213 patients in the primary study population who received a 5-ASA ± CS by 30 days after diagnosis, 40% (n = 86) were PGA inactive and were CS-free/rescue-free at 1 year after diagnosis (primary outcome measure) (Table 3). An additional 15% (n = 31) were PGA mild and were CS-free/rescue-free at 1 year (secondary outcome measure). The remaining 45% (n = 96) of patients required additional rescue therapies (n = 79), and/or had moderate or severely active disease (n = 20), and/or were using CS at 1 year following diagnosis (n = 29); note that these latter groups are not mutually exclusive. Of the 79 patients who received additional rescue therapies, 76 received an immunomodulator (6-mercaptopurine or azathioprine or methotrexate), 3 received calcineurin inhibitors (cyclosporine or tacrolimus), 23 received infliximab, and 7 underwent surgery. These therapies were again not mutually exclusive.

When we further analyzed outcomes at 1 year by initial treatment group, we identified a significant difference between patients treated with 5-ASA monotherapy at the time of diagnosis, compared with those patients who were treated with CS induction and 5-ASA maintenance. Overall, 47% of patients treated with 5-ASA alone were in CS-free remission at 1 year, compared with 35% of patients treated with steroids and maintained on 5-ASA. Less favorable (“other”) outcomes were seen in 35% of patients treated with 5-ASA monotherapy at the time of diagnosis, compared with 54% of patients who were treated with CS induction and 5-ASA (P = 0.017). Although similar numerical differences are seen for patient outcomes when grouped by disease severity (mild, moderate/severe) at diagnosis, the differences do not achieve statistical significance.

In a separate analysis, we looked at the 1-year outcome of the 29 patients who received CS only by 30 days who then went on to receive 5-ASA without the addition of rescue therapies by the end of the first 3 months following diagnosis. Although this subgroup of patients was excluded from the primary study population, we felt that it was a clinically relevant group and warranted further attention. Twenty-seven of these 29 patients (93%) were either moderate or severe by PGA at diagnosis. At 1 year, 45% (13/29) were CS-free/rescue-free and PGA inactive and 1 patient (3%) was CS-free/rescue-free PGA mild.

Factors Affecting Outcomes

Within our study population, we looked at clinical and demographic variables that may have been associated with CS-free/rescue-free inactive disease at 1 year following diagnosis of UC (Table 4). Using a simple logistic regression model comparing only this primary outcome against all other outcomes combined, we found no significant associations with respect to age at diagnosis, sex, dose of 5-ASA used, initial PGA, and initial laboratory values recorded at diagnosis. We did however find that patients receiving rectal therapy by 1 year are less likely than patients who did not receive rectal therapy to be in CS-free/rescue-free remission at 1 year.

DISCUSSION

Our study demonstrates that 40% of pediatric patients with newly diagnosed UC treated with 5-ASA with or without CS by 30 days following diagnosis have inactive disease, no longer require CS, and have avoided escalation of therapy or colectomy at 1 year. These data reflect the experience from a large multicenter inception cohort in the United States and Canada, and likely are representative of real-world experience. We did not find any presenting laboratory or clinical features, which were associated with a higher likelihood of achieving favorable outcomes following initiation of 5-ASA medications for the treatment of UC. It should be noted that additional laboratory markers that may demonstrate improved correlation with endoscopic inflammation such as C-reactive protein and fecal calprotectin were not systematically collected and were not included in our analysis. We would also like to remind the reader that our study cohort included only patients receiving oral 5-ASA with or without CSs within the first 30 days following diagnosis, and excluded a presumably sicker subset of patients, for whom additional rescue treatments were received during this time frame.

It is difficult to directly compare our results to other studies looking at efficacy of 5-ASA medications for the treatment of UC because of differences in study design, patient population, specific formulations, and dosages of 5-ASA used, as well clinical and/or endoscopic definitions of remission. Nonetheless, published studies focusing on adult patients at a 1-year endpoint report that efficacy of 5-ASA for the treatment of UC ranges from 26% to 63% (6–8). As stated previously, the pediatric-specific literature looking at outcomes of 5-ASA medications is limited to small studies with short duration of follow-up, and somewhat larger observational studies. Favorable outcomes, which have thus been variably defined for pediatric patients with UC receiving 5-ASA medications, have ranged from 39% to 49% (4,5). Although some studies in adults report mucosal healing as a clinical endpoint, it should be noted that this information was not available for our study population.

There have been no published pediatric-specific studies on optimal dosing schedules of 5-ASA medications for the treatment of children with UC. As such in our study, we found that the dose of 5-ASA used did not correlate to clinical severity of disease at presentation as per initial PGA or laboratory markers including hemoglobin, platelet count, ESR, and albumin. The mean daily dosage of 5-ASA compounds was 52 mg/kg, although the range was wide. Approximately, 23% of children receiving 5-ASA had a daily dose of ≥60 mg · kg−1 · day−1. In the Registry, the specific formulation of 5-ASA preparation is not recorded.

There have been various adult studies comparing 1 or more 5-ASA formulations or doses (9–15). The ASCEND II trial (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA) suggested that higher dosing schedules may provide additional clinical benefit in some patients (11). The study was a randomized double-blind controlled trial looking at the efficacy of 4.8 versus 2.4 g/day of mesalamine in 386 adults with active UC and found that treatment success (defined as clinical response or remission from baseline at week 6 evaluated by PGA) was 32% versus 40% for patients with mild UC favoring patients receiving a higher dose (P = NS). For patients with moderate disease activity, however, treatment success was significantly increased in patients receiving the higher dose (59% vs 72%; P = 0.036) (11). Although our study did not find a difference in outcome between those receiving <60 mg · kg−1 · day−1 of 5-ASA and those receiving higher doses, it should be noted that our study does not reflect a formal clinical trial and any conclusions about dose effect should be interpreted with caution.

Likewise, adherence to 5-ASA dosing schedules has become an increasingly important consideration, and has gained focus in the pediatric literature (16–19) because of the potential for significant negative effects on outcome. A pediatric study has shown that baseline adherence to 5-ASA regimens is as low as 43% (16). Adherence, however, was not a controlled variable in our study but is clearly a factor that needs consideration in the interpretation of our results because it would be anticipated that improved adherence would perhaps improve overall outcomes.

We found that rectal therapy was common in those patients treated with 5-ASA. Although there are no published pediatric trials addressing potential effects of rectal therapy in UC, adult studies have shown that at various endpoints, including short-term (1 month) (20–23) and long-term (1 year) (24,25), rectal therapy may have positive effects on clinical outcomes. Although our data show that 17% of the study population received various rectal therapies by 30 days following diagnosis, and cumulatively over the first year, 32% had received rectal therapies, we did not specifically control for their use as frequency of administration, and specific formulation including whether the rectal therapy was 5-ASA versus steroid-based was not routinely available. As described above, the registry data provide information only in a yes-no format about whether rectal therapy was used. With respect to rectal therapy usage, we did, however, find in a simple logistic regression model comparing our primary outcome against all other outcomes that rectal therapy usage by 1 year was associated with poorer outcomes. Given the limitations of our database described above, it is difficult to know how best to interpret this finding and therefore warrants further study.

A potential important factor in our study was that disease activity was measured by PGA, not the validated Pediatric UC Activity Index (PUCAI) (26–28) that was introduced into clinical practice in 2007, 5 years after data for the present study was initially collected. Data from development of the PUCAI, however, have shown excellent correlation between PGA and PUCAI (28,29).

In summary, 40% of pediatric patients with UC treated with 5-ASA with or without CS by 30 days following diagnosis have inactive disease, no longer require CS, and have avoided escalation of therapy or colectomy at 1 year. Further pediatric studies will be needed to address whether increased patient adherence to 5-ASA regimens and possibly higher 5-ASA dosing schedules, including the concomitant use of topical therapies, may be needed to improve outcomes. In addition, although there has been an increasing body of literature identifying clinical, biological, and genetic markers that predict risk of disease, and disease phenotype (30–33), additional research specifically looking at possible markers to identify patient subsets most likely to respond favorably to 5-ASA compounds may help guide medical decision making.

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